Archives of Toxicology

, Volume 86, Issue 1, pp 17–25 | Cite as

Threshold of toxicological concern values for non-genotoxic effects in industrial chemicals: re-evaluation of the Cramer classification

  • H. Kalkhof
  • M. Herzler
  • R. Stahlmann
  • U. Gundert-RemyEmail author
Regulatory Toxicology


The TTC concept employs available data from animal testing to derive a distribution of NOAELs. Taking a probabilistic view, the 5th percentile of the distribution is taken as a threshold value for toxicity. In this paper, we use 824 NOAELs from repeated dose toxicity studies of industrial chemicals to re-evaluate the currently employed TTC values, which have been derived for substances grouped according to the Cramer scheme (Cramer et al. in Food Cosm Toxicol 16:255–276, 1978) by Munro et al. (Food Chem Toxicol 34:829–867, 1996) and refined by Kroes and Kozianowski (Toxicol Lett 127:43–46, 2002), Kroes et al. 2000. In our data set, consisting of 756 NOAELs from 28-day repeated dose testing and 57 NOAELs from 90-days repeated dose testing, the experimental NOAEL had to be extrapolated to chronic TTC using regulatory accepted extrapolation factors. The TTC values derived from our data set were higher than the currently used TTC values confirming the safety of the latter. We analysed the prediction of the Cramer classification by comparing the classification by this tool with the guidance values for classification according to the Globally Harmonised System of classification and labelling of the United Nations (GHS). Nearly 90% of the chemicals were in Cramer class 3 and assumed as highly toxic compared to 22% according to the GHS. The Cramer classification does underestimate the toxicity of chemicals only in 4.6% of the cases. Hence, from a regulatory perspective, the Cramer classification scheme might be applied as it overestimates hazard of a chemical.


Cramer classification TTC values Industrial chemicals Improvements Repeated dose toxicity 



This work was supported by a grant from German Federal Ministry of Environment, Radiation Protection and Nature Conservation, Germany; Project No. UBA/Z 6, Kap. 1602/Tit.685 04, 90381-547. We thank Dr. Ulrike Bernauer, BfR, for her comments on an earlier version of this paper. Data presented in this publication are part of the Master Thesis of Dr. Hoger Kalkhof prepared during the Master educational program at Charité–Universitätsmedizin Berlin.

Conflict of interest

The authors declare that they have no conflicts of interest.


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • H. Kalkhof
    • 1
  • M. Herzler
    • 2
  • R. Stahlmann
    • 1
  • U. Gundert-Remy
    • 1
    • 2
    Email author
  1. 1.Institute for Clinical Pharmacology and Toxicology, Charité–Universitätsmedizin BerlinBerlinGermany
  2. 2.Federal Institute for Risk Assessment, BfR, Bundesinstitut fuer RisikobewertungBerlinGermany

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